Getting vaccinated and boosted dramatically increases the likelihood of surviving a case of COVID-19, but many risk factors—like being biologically male—are outside of people’s control. In the U.S., 20% more men have died from COVID-19 than women, according to data from the U.S. Centers for Disease Control and Prevention. Scientists theorize that the difference in risk between the two sexes may, in part, come down to the hormone estrogen, which plays a role in the immune system.
New research published in BMJ Open on Feb. 14 links estrogen levels to women’s likelihood of dying after they contract COVID-19. In the study, researchers looked at Swedish national health registry data from more than 16,000 women, ages 50 to 80, who had tested positive for COVID-19 between Feb. 4 and Sept. 14 of 2020. Most had gone through menopause, a time during which estrogen typically drops.
Researchers were particularly interested in the women in the group who were taking medications that affect estrogen levels: 227 were on endocrine therapy, a treatment for breast cancer that lowers estrogen, and about 2,500 were undergoing hormone replacement therapy, which increases estrogen levels in order to reduce menopausal symptoms.
After researchers factored in the women’s comorbidities, age, and socio-economic factors, they found that women who were taking medications that raised estrogen levels were about half as likely to die from COVID-19 as women who weren’t taking medications that affect estrogen. (There was also an initial link between taking estrogen-lowering medications and having an increased risk of dying from COVID-19, but after factoring in the confounding variables, it was not significant.)
The finding fits with those from other observational studies that have also linked high estrogen levels to a lower risk of becoming seriously ill from COVID-19, says Dr. Franck Mauvais-Jarvis, director of the Sex-Based Medicine Laboratory at Tulane University (who was not involved in the study). Estrogen—and the hormone progesterone, to a lesser extent—is believed to be involved in the body’s immune response and may limit inflammation, he says. In COVID-19, inflammation can trigger a “cytokine storm,” a dangerous condition in which the immune system can get overwhelmed.
Other research suggests that estrogen may also affect spike protein receptors, which SARS-CoV-2—the virus that causes COVID-19—uses to get into cells, says Dr. Malin Sund, a professor at Umeå University in Sweden and co-author of the new study.
However, as Sund and her fellow authors point out, randomized clinical trials are necessary to determine whether the link is causal, and if artificially increasing estrogen can protect patients from COVID-19. The new study is not without drawbacks; for instance, the researchers were unable to check the women’s hormone levels over time.
Sund emphasizes that people should not experiment with altering their estrogen levels; raising estrogen levels can have side effects, such as an increased risk of breast cancer. Conversely, “women who have had breast cancer should absolutely not stop taking their endocrine therapy based on this study because they really need their treatment for breast cancer,” says Sund. “The best thing they can do is get vaccinated.”
Many diseases affect men and women differently, but throughout much of history, scientific research has focused on males alone. The U.S. National Institutes of Health didn’t make it an official policy to include women in clinical trials until 1989, and it didn’t require grant applicants to balance sex in research on cells and animals until 2014.
Studying sex differences and disease shouldn’t stop with COVID-19, Mauvais-Jarvis says. “There are a lot of diseases—not just COVID-19—that are characterized by differences between men and women,” he says.
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